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Metabolomics. 2011 Sep;7(3):353-362. Epub 2010 Nov 25.

Metabolic profiling of HepG2 cells incubated with S(-) and R(+) enantiomers of anti-coagulating drug warfarin.


Warfarin is a commonly prescribed oral anticoagulant with narrow therapeutic index. It achieves anti-coagulating effects by interfering with the vitamin K cycle. Warfarin has two enantiomers, S(-) and R(+) and undergoes stereoselective metabolism, with the S(-) enantiomer being more effective. We reported the intracellular metabolic profile in HepG2 cells incubated with S(-) and R(+) warfarin by GCMS. Chemometric method PCA was applied to analyze the individual samples. A total of 80 metabolites which belong to different categories were identified. Two batches of experiments (with and without the presence of vitamin K) were designed. In samples incubated with S(-) and R(+) warfarin, glucuronic acid showed significantly decreased in cells incubated with R(+) warfarin but not in those incubated with S(-) warfarin. It may partially explain the lower bio-activity of R(+) warfarin. And arachidonic acid showed increased in cells incubated with S(-) warfarin but not in those incubated with R(+) warfarin. In addition, a number of small molecules involved in γ-glutamyl cycle displayed ratio variations. Intracellular glutathione detection further validated the results. Taken together, our findings provided molecular evidence on a comprehensive metabolic profile on warfarin-cell interaction which may shed new lights on future improvement of warfarin therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-010-0262-3) contains supplementary material, which is available to authorized users.

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